Basically substituted (1h,3h)-quinazoline-2-thion-4-one derivatives

ABSTRACT

The present invention relates to new, pharmacologically valuable, basically substituted (1H,3H)-quinazoline-2-thion-4-one derivatives having the structural formula   WHEREIN R&#39;&#39; is a radical selected from the group consisting of N-(pchlorphenyl)-piperazino, N-(3,4-dimethoxybenzyl)-piperazino; R1 is an alkoxy group having 1-4 carbon atoms attached to positions 6,7 or 6,7,8; R2 is an alkoxy group having 1-4 carbon atoms; M IS AN INTEGER SELECTGED FROM THE GROUP CONSISTING OF 1,2 AND 3 N IS AN INTEGER SELECTED FROM THE GROUP CONSISTING OF 2 AND 3; OR THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, AND TO A PROCESS OF PRODUCING SAID DERIVATIVES BY ACYLATING, OPTIONALLY IN THE PRESENCE OF AN ACID-BINDING AGENT, (1H,3H)-quinazoline2-thion-4-one derivatives having the structural formula   Wherein R&#39;&#39;, R1 and n have the above given meanings, with an alkoxy benzoic acid having the structural formula   WHEREIN R2 and m have the meanings set out hereinabove, or a functional derivative thereof.

United States Patent [191 Beyerle et al.

[ Dec. 17, 1974 1 1 BASICALLY SUBSTITUTED lI-I,3I-I)-QUINAZOLINE-2-THION-4-ONE DERIVATIVES [75] Inventors: Rudi Beyerle, Bruchkobel,

Germany; Adolf Stachel, deceased, late of Offenbach, Germany by Ingeburg Lydia Katharina Stachel, executrix; Rolf-Eberhard Nitz, Bergen-Enkheim; Josef Scholtholt, Frankfurt-Fechenheim, both of Germany [73] Assignee: Cassella Farbwerke Mainkur Aktiengesellschaft, Frankfurt, Germany [22] Filed: Apr. 17, I973 [21] Appl. No.: 351,832

Related US. Application Data [62] Division of Ser. No. 187,562, Oct. 7, 1971, Pat. No.

[30} Foreign Application Priority Data Oct. 15, 1970 Germany 2050640 [52] US. Cl 260/2565 R [51] Int. Cl C07d 51/48 [58] Field of Search 260/2565 R, 256.4 Q

[56] References Cited UNITED STATES PATENTS 3,738,985 6/1973 Beyerle et a1 260/2564 Q 3,740,398 6/1973 Beyerle et a1 260/2564 Q 3,793,320 2/1974 Beyerle et a1 260/247.1

Primary Examiner-Richard J. Gallagher Attorney, Agent, or FirmFrancis M. Crawford 57 ABSTRACT The present invention relates to new, pharmacologically valuable, basically substituted (lH,3H)-quinazo- 1ine-2-thion-4-one derivatives having the structural formula k not. wherein Wherein R, R, and n have the above given meanings, with an alkoxy benzoic acid having the structural formula wherein R and m have the meanings set out hereinabove, or a functional derivative thereof.

5 Claims, N0 Drawings BASICALLY SUBSTITUTED (1H,3H)-QUINAZOLINE-2-THION-4-ONE DERIVATIVES The present application is a division of our US. pa- 5 tent application Ser. No. 187,562, filed Oct. 7, 1971, now matured into US. Pat. No. 3,793,320.

The present invention relates to new, pharmacologically valuable, basically substituted (ll-l,3l-l)-quina2oline-2-thion-4-one derivatives having the structural formula (I) c N'CHg-CI -CH2-R-' 5 (R011 l =s 0 (b0 H 1 (B3)! wherein R is R, is an alkoxy group having 1-4 carbon atoms attached to positions 6,7 or 6,7,8; R is an alkoxy group having 1-4 carbon atoms;

X stands for a radical selected from the group consisting of 4-chloro and 3,4-dimethoxy;

m is an integer selected from the group consisting of 1,2 and 3 n is an integer selected from the group consisting of 2 and 3;

or the pharmaceutically acceptable salts thereof, and

to a process of producing said derivatives by acylating, optionally in the presence of an acid-binding agent, (1H.3H)-quinazoline-2-thion-4-one derivatives having the structural formula mula wherein R and m have the meanings set out hereinabove, or a functional derivative thereof.

The 3-('y-amino-B-hydroxypropyl)-( 1H,3H)- quinazoline-2-thion-4-ones required as starting material are prepared analogously to the description given in the Journal Helvetia Chimica Acta (1967), 1,440, by reacting the correspondingly substituted 0- alkoxycarbonyl-phenylisothiocyanates with 3-7-amino- ,B-hydroxypropylamines.

The (1H,3H)-quinazoline-2-thion-4-one derivatives according to the present invention are valuable pharmaceuticals. In particular, they are excellent coronary dilators and, in this respect, superior to other known substances of this kind.

With respect to the change in the oxygen tension in the coronary veinous blood, the pharmacological investigation of the vasodilator action on the coronary vessels was carried out in dogs according to the methods described by W. K. A. Schaper and his co-workers (see W. K. A. Schaper, R. Xhonneux, and .l. M. Bogaard Uber die kontinuierliche Messung des Sauerstoffdruckes im venoesen Coronarblut (Naunyn- Schmiedebergs Arch. exp. Path. u. Pharmak. 245, 383-389 (1963)). The test preparations were applied intravenously to the narcotized and spontaneously breathing animals. On these test conditions the dilatation of the coronary arteries caused by the test substances along with the increase in the coronary blood flow led to an increase in the oxygen tension in the coronary veinous blood. This oxygen tension was measured according to polarographic methods by means of a platin electrode of the Gleichmann-Lubbers type (see U. Gleichmann and D. W. Luebbers Die Messung des Sauerstoffdruckes in Gasen und Fluessigkeiten mit der Platin-Elektrode unter besonderer Beruecksichtigung der Messung im Blut," Pflugers Arch. 271, 431455 (1960)). The heart rate was continuously measured by electronic methods from systolic peaks of the arterial blood pressure. The arterial blood pressure was measured in the known manner in the femoral artery with the aid of an electromanometer of the Statham-straingauge type.

(R1)n 50 The following table gives the results of the pharmaco- :S OH logical investigations which were carried through. The f preparations were tested in the form of their respective H hydrochlorides:

Maximal Change Preparation LD 50 Dosage Maximal Increase Maximal Change in the Blood g./kg. mg./kg. in Oxygen Tension in the Heart Presure Mouse |.v. in the Corona Rate (systolic/ t.v. Veinous Bl diastolic) in in Minutes in in Minutes in '7: in Minutes 3-[y-diethylamino-B-(3,4,5- trimethoxybenzoxwiprcipyl} 0.05 77 30 16 20 -7/l4 2 6,7,8-trimethoxy-(l ,3 quinazoline-2-thion-4-one 3-[y-di-n-propylamino-[3- (3.4,5-trimethoxybenzoxy)- 0.05 46 50 25 10 5/:0 30

pro y1]-6.7.8-trimethoxy- Ill 3H )-quinazoline- 2-thion-4-one Continued g./kg.

Mouse i.v.

Preparation Dosage mglkg. 1.v.

Maximal Increase in Oxygen Tension in the Corona Veinous Bl Maximal Change in the Blood Pressure (systolic/ diastolic) in Minutes Maximal Change in the Heart Rate in Minutes in 7: in Minutes in 7:

3-[ -N-methyl-N-all lamino- 1345.4,5-trimethoxy enzoxy)- propyl]-6,7.8-trimethoxylH, 3H)-quinazoline-2-thion- 4-one 3-[ -N-methyl-N-benzylamino B-(3,4,5-trimethoxybenzoxy)- l 3Hl-quinazoline-2-thion- 4-one 3-[y-N-eth 'l-N-cyclohexylamino-[3% .4.5-trimethoxybenzoxy)-propyl]-6.7,8- trimethox lH, 3H)-quinazoline-2-t ion-4-one 3-['y-piperidino-/3-(3.4,5-

trimethoxybenzox )l prosiyll- 6,7,8-trimethoxy-l ,3 quinazoline-2-thion-4-one 3-[ 'y-morpholino-B-( 3,4,5- trimethoxybenzoxy )l-ffligyl 6,7,8-trimethoxy-(l .3 quinazoline 2-thion-4-one H l-quinazoline-Z-thion- -one iperaEinMb-eB-(S, H tnmet oxy nzoxy ro y 6.7.8-trimethoxy-( 1423;) quinazoline-2-thion-4-one 4-one 3-1 ymorpholino-B- (3,4.5-trimethoxybenzoxy )-propyl]- 6,7-dimethoxy-t lH,3H)- quinazoline-Z-thion- 4-one 3-[y-hexamethyleneimino-/3-( 3,4,5-trimethoxybenzoxy)- prop1yl]-6,7,8-trimet oxy-t lH,3l-l)- quinazoline-2-thion- 4-one In the preparation of dragees and tablets containing as essential active ingredient the quinazoline derivatives of our invention these substances may be admixed with the conventional solid tabletting adjuvants, such as starch, lactose, talc and the like. Any of the tabletting materials and carriers customary in pharmaceutical practice may be employed.

For the preparation of the injection solutions the hydrochlorides of the quinazoline derivates are particu- EXAMPLE 39.7 g. (0. 1 mol) 3-(y-diethylamino-B- hydroxypropyl )-6,7 ,8-trimethoxy-( 1H,31-1 )-quinazoline-2-thion-4-one are dissolved in 250 c.c. chloroform and admixed with 11.1 g. (0.11 mol) triethylamine. Subsequently, while stirring at room temperature, a solution consisting of 25.3 g. (0.11 mol) 3,4,5- trimethoxybenzoyl chloride in 80 c.c. chloroform is added dropwise during minutes and stirring is continued for one hour at room temperature. The reaction mixture is heated to the boil and stirred for 6 hours under reflux. After cooling down it is evaporated to dryness in vacuo. The residue is dissolved with stirring in dilute hydrochloric acid and the thusly obtained solution is filtered so as to become limpid. The aqueous hydrochloric acid solution is then rendered alkaline by the addition of aqueous sodium hydroxide solution and the oily, separating reaction product is dissolved in ethyl acetate. After drying over potassium carbonate, one obtains by the introduction of anhydrous gaseous hydrogen chloride into the ethyl acetate solution the hydrochloride of the 3-[y-diethylamino-B-(3,4,5-

The 3-( y-diethylamino-B-hydroxypropyl )-6,7,8- trimethoxy-( lH,3-H )-quinazoline-2-thion-4-one required as starting material may be prepared as follows:

28.3 g. (0.1 mol) 2,3,4-trimethoxy-6- methoxycarbonyl-phenylisothiocyanate, prepared by reacting analogously to the description given in Journal of Organic Chemistry 27 (1962), 3702 the methyl- 3,4,5-trimethoxy anthranilate with thiophosgene, are dissolved in 200 c.c. anhydrous diethyl ether and, while stirring at room temperature, admixed with a solution consiting of 14.6 g. (0.1 mol) 'y-diethylamino-B- hydroxypropylamine in c.c. anhydrous diethyl ether. Stirring is continued for 2 hoursat room temperature, subsequently, the reaction product which separates in the form of crystals is sucked off and obtained is the 3- (y-diethylamino-B-hydroxypropyl)-6,7,8-trimethoxy- (1H,3H)-quinazoline-2-thion-4-one in the form of colorless needles melting at 146. Yield: 33 g. (=83 percent of the theoretical) Analogously to the above process the following starting materials may be prepared:

General formula:

o 1| (RI) n N-CH -(fiH-CH -R M.P., (Rl)n R degrees 6,7-(0 CH3) 2 N(C;1H5)2 -167 6,7,8-(0 011:)3 -N (n- CaH1)1 153-155 6,7,8-(0 oHm N(CH3)CH2-CII:C 111 137-138 6,7,8-(0 CH3): N CH3) 01120 115 113-114 6,7,8-(0 CHa)a 173 6,7,8-(0 CH3); (|)CH3 157-159 N/ iv- CH:O o 1-1,

e,7,s-(o CHa)a 213421 N N- Cl 6,7,8-(O CHa)a N/ \l 172 trimethoxybenzoxy)-propyl]-6,7,8-trimethoxy- 1H,3H )-quinazoline-2-thion-4-one in the form of colorless needles melting at 154 156.

Yield: 43 g. 68.5 percent of the theoretical).

Analogously to the description given in para 1 of this 65 example, the following compounds of the present invention are prepared from the above starting materials:

General formula:

' 1 i i (hy- R1 n (Ron R i fis' 3,4,5-(OCH;)3 r- 00111): N czn 2 1 130 3,4,5-(OCH3): (an-(0on3 s 3,4,5-(OCH3).1 6,7,8-(00113); N(l1-C3H7)2 119 -(OCHm ens-(0cm); N cI+I cH (1112 1 75 3,4,5-(0CHm ens- 0cm --N(CH3)CH2C6['I5 130 3,4,5-(OCH3): 6,7,8-(OCH3); i 179 N(C2H5) H 3,4,5-(00113); 6,7,8-(OCH3)3 I 156-160 3,4,54001193 eggs-(0cm 203 -(0CHm mit 3): 138-140 3,4,54001193 smstocnm OOH 260 m N /NC [IQ- OCHa a s- 001ml ans-(00111); C1 17mm 3,4,5-(00119: ans- 0cm C 163 1 Decomposition.

What is Claim i5; m is an integer selected from the group consistingof 1. A compound of the structural formula 1, 2 d 3;

O n is an integer selected from the group consisting of H X 2 and 3 or the pharmaceutically acceptable salts cH, cH-omN NQ thereof. I (B1) g 2. A compound according to claim 1, wherein R is N/ l a methoxy group.

1 C0 3. A compound according to claim 1, wherein R is H a methoxy group.

4. 3-[y-(N-(3,4-Dimethoxybenzyl)piperazinoH3- O (3,4,5-trimethoxybenzoxy)-propyl]-6,7,8-trimethoxy- W V (lH,3H)-quinazoline-2-thion-4-one, or the pharmawherein ceutically acceptable salts thereof.

, R is an alkoxy group having 1 4 carbon atoms at- 3[7'(N 'p'chlorophenyl'plprazmoHM3'45' tached to position 6 7 or 6 7 8; trimethoxyb enzox y)-prop l]-6,7,8-tr1methoxy- R2 is an alkoxy group havin 1 4 carbon atoms; (l13HH1mazohne'z'thlon'4 one or the pharma' X stands for a radical selected from the group conceuncany acceptablf i i i sisting of 4-chloro and 3,4-dimethoxy; 

1. A COMPOUND OF THE STRUCTURAL FORMULA
 2. A compound according to claim 1, wherein R1 is a methoxy group.
 3. A compound according to claim 1, wherein R2 is a methoxy group.
 4. 3-( gamma -(N''-(3,4-Dimethoxybenzyl)-piperazino)- Beta -(3,4, 5-trimethoxybenzoxy)-propyl)-6,7,8-trimethoxy-(1H,3H)-quinazoline-2-thion-4 -one, or the pharmaceutically acceptable salts thereof.
 5. 3( gamma -(N''-p-Chlorophenyl-piperazino)- Beta -(3,4,5-trimethoxybenzoxy)-propyl)-6,7,8-trimethoxy-(1H,3H)-quinazoline-2 -thion-4-one, or the pharmaceutically acceptable salts thereof. 